During evolution, mammalians establish gradually a set of signaling mechanisms for apoptosis which can induce programmed death of individual cells. The underlying theory is that ligands of lethal cells interact with the death receptors on cell surfaces, which induces apoptosis of cells. Such beneficial apoptosis plays a critical physiological role in the elimination of activated lymphocytes at the end of an immune response and in the elimination of virus-infected cells and oncogenically transformed cells. The examples thereof include the interaction between TNF and receptor TNFR, and the interaction between FasL and receptor Fas/Apo1/CD95.
The activated death receptors are directly involved in the cascade reactions of cell apoptosis. They can induce the apoptosis of various cancer cells, and are potential anti-cancer factors. Although TNF and FasL can induce the apoptosis of cancer cells, they cause severe toxic and side effects in anti-cancer therapy. Injection of TNF can lead to fatal inflammatory responses similar to septic shocks. This response is mainly mediated by NF-κB, a pre-transcriptional factor, which is located in vascular endothelial cells and macrophages and which is activated by TNF. Anti-Fas antibody can induce a Fas-dependent cell apoptosis in liver tissues, and cause fatal liver damages.
Wiley et al. discovered TNF-related apoptosis-inducing ligand (TRAIL) based on the sequence identity with TNF and FasL in 1995. TRAIL can induce apoptosis by interacting with death receptor DR4 or DR5. Unlike TNF and FasL, the mRNA of TRAIL is constitutively expressed in many normal human tissues. This indicates a physiological mechanism by which TRAIL induces apoptosis of cancer cells while sparing normal cells. These mechanisms include: expression of inhibitory receptors, ability of competing with DR4 and DR5 for binding to ligands, ability of TRAIL to interact with three receptors DcR1, DcR2 and DPG. Therefore, the toxicity of TRAIL is less than TNF and FasL.